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Portrait of Sara Snogerup Linse

Sara Linse


Portrait of Sara Snogerup Linse

Structural requirements of anticoagulant protein S for its binding to the complement regulator c4b-binding protein


  • TK Giri
  • Sara Linse
  • Pablo Garcia de Frutos
  • Tomio Yamazaki
  • BO Villoutreix
  • Björn Dahlbäck

Summary, in English

The vitamin K-dependent anticoagulant protein S binds with high affinity to C4b-binding protein (C4BP), a regulator of complement. Despite the physiological importance of the complex, we have only a patchy view of the C4BP-binding site in protein S. Based on phage display experiments, protein S residues 447-460 were suggested to form part of the binding site. Several experimental approaches were now used to further elucidate the structural requirements for protein S binding to C4BP. Peptides comprising residues 447-460, 451460, or 453-460 of protein S were found to inhibit the protein S-C4BP interaction, whereas deletion of residues 459-460 from the peptide caused complete loss of inhibition. In recombinant protein S, each of residues 447-460 was mutated to Ala, and the protein S variants were tested for binding to C4BP. The Y456A mutation reduced binding to C4BP similar to10-fold, and a peptide corresponding to residues 447-460 of this mutant was less inhibitory than the parent peptide. A further decrease in binding was observed using a recombinant variant in which a site for N-linked glycosylation was moved from position 458 to 456 (Y456N/N458T). A monoclonal antibody (HPSf) selective for free protein S reacted poorly with the Y456A variant but reacted efficiently with the other variants. A second antibody, HPS 34, which partially inhibited the protein S-C4BP interaction, reacted poorly with several of the Ala mutants, suggesting that its epitope was located in the 451-460 region. Phage display analysis of the HPS 34 antibody further identified this region as its epitope. Taken together, our results suggest that residues 453-460 of protein S form part of a more complex binding site for C4BP. A recently developed three-dimensional model of the sex hormone-binding globulin-like region of protein S was used to analyze available experimental data.


  • Biophysical Chemistry
  • Clinical Chemistry, Malmö

Publishing year







Journal of Biological Chemistry





Document type

Journal article


American Society for Biochemistry and Molecular Biology


  • Medicinal Chemistry
  • Pharmacology and Toxicology



Research group

  • Clinical Chemistry, Malmö


  • ISSN: 1083-351X